Steps Forward: Review and Recommendations for Research on Walkability, Physical Activity and Cardiovascular Health.
Built environments that support walking and other physical activities have the potential to reduce cardiovascular disease (CVD). Walkable neighborhoods-characterized by density, land use diversity, and well-connected transportation networks-have been linked to more walking, less obesity, and lower coronary heart disease risk. Yet ongoing research on pedestrian-friendly built environments has the potential to address important gaps. While much of the literature has focused on urban form and planning characteristics, additional aspects of street-scapes, such as natural and architectural amenities, should also be considered. Promising future directions include (1) integration of multiple built environment measures that facilitate an understanding of how individuals perceive and act within their environment; (2) examination of both the daily physical activities that are most feasibly influenced by the local environment and those more deliberate or vigorous patterns of physical activity that are most predictive of CVD; (3) consideration of multiple pathways that could mediate a link between walkability and CVD, including not only physical activity, but also air quality improvements from reduced vehicle mileage and enhanced neighborhood social cohesion from unplanned interactions; (4) testing competing hypotheses that may explain interactions of built environment characteristics with each other and with personal barriers to walking; (5) stronger conceptualization of the multiple neighborhoods or activity spaces that structure opportunities for physical activity throughout the day; (6) collecting and strategically analyzing longitudinal data to support causal inference; and (7) studying neighborhood preferences and selection to move beyond biased assessments of neighborhood health effects. While walkability has been linked to health-related behaviors and CVD risk factors, the implications of the observed correlations are not yet clear. New theoretical insights, measurement technologies, and built environment changes represent opportunities to enhance the evidence base for bringing health promotion and cardiovascular disease prevention into the conversation about how communities are planned and built.


Evolution of nonlinear cosmological perturbations.
We define fully nonperturbative generalizations of the uniform density and comoving curvature perturbations, which are known, in the linear theory, to be conserved on sufficiently large scales for adiabatic perturbations. Our nonlinear generalizations are defined geometrically, independently of any coordinate system. We give the equations governing their evolution on all scales. Also, in order to make contact with previous works on first- and second-order perturbations, we introduce a coordinate system and show that previous results can be recovered, on large scales, in a remarkably simple way, after restricting our definitions to first and second orders in a perturbative expansion.


Longitudinal sleep problem trajectories are associated with multiple impairments in child well-being.
This study examined whether distinct sleep problem trajectories from infancy through middle childhood were associated with multiple aspects of child well-being at ages 10-11 years. Data were from the first six waves of the Longitudinal Study of Australian Children - Birth Cohort (5,107 children recruited at birth). Caregivers reported on child sleep problems at each time point. A combination of caregiver-reported, teacher-reported and child-completed tasks were used to index child well-being outcomes at ages 10-11 years including emotional/behavioural functioning (internalizing and externalizing symptoms; self-control), health-related quality of life, cognitive skills and academic achievement. Latent class analysis identified five distinct sleep problem trajectories over time: persistent sleep problems through middle childhood (7.7% of the sample), limited infant/preschool sleep problems (9.0%), increased middle childhood sleep problems (17.0%), mild sleep problems over time (14.4%) and no sleep problems (51.9%). Compared to those with no sleep problems, children with persistent sleep problems had the greatest impairments across all outcomes except cognitive skills (perceptual reasoning), with moderate to large effect sizes. Children with increased middle childhood sleep problems similarly experienced greater internalizing and externalizing symptoms and worse quality of life, but few academic impairments. Both the limited infant/preschool sleep problems and mild increases over time trajectories also showed internalizing concerns and worse caregiver-reported quality of life, although effects were smaller than the other sleep trajectories. The linkages between sleep problems and negative child outcomes across domains underscore the importance of early identification and targeted intervention to address sleep problems and promote child well-being.


Positive genetic correlation between brain size and sexual traits in male guppies artificially selected for brain size.
Brain size is an energetically costly trait to develop and maintain. Investments into other costly aspects of an organism's biology may therefore place important constraints on brain size evolution. Sexual traits are often costly and could therefore be traded off against neural investment. However, brain size may itself be under sexual selection through mate choice on cognitive ability. Here, we use guppy (Poecilia reticulata) lines selected for large and small brain size relative to body size to investigate the relationship between brain size, a large suite of male primary and secondary sexual traits, and body condition index. We found no evidence for trade-offs between brain size and sexual traits. Instead, larger-brained males had higher expression of several primary and precopulatory sexual traits--they had longer genitalia, were more colourful and developed longer tails than smaller-brained males. Larger-brained males were also in better body condition when housed in single-sex groups. There was no difference in post-copulatory sexual traits between males from the large- and small-brained lines. Our data do not support the hypothesis that investment into sexual traits is an important limiting factor to brain size evolution, but instead suggest that brain size and several sexual traits are positively genetically correlated.


Isolation, growth and genome of the Rhodothermus RM378 thermophilic bacteriophage.
Several bacteriophages that infect different strains of the thermophilic bacterium Rhodothermus marinus were isolated and their infection pattern was studied. One phage, named RM378 was cultivated and characterized. The RM378 genome was also sequenced and analyzed. The phage was grouped as a member of the Myoviridae family with A2 morphology. It had a moderately elongated head, with dimensions of 85 and 95 nm between opposite apices and a 150 nm long tail, attached with a connector to the head. RM378 showed a virulent behavior that followed a lytic cycle of infection. It routinely gave lysates with 10(11) pfu/ml, and sometimes reached titers as high as 10(13) pfu/ml. The titer remained stable up to 65 °C but the phage lost viability when incubated at higher temperatures. Heating for 30 min at 96 °C lowered the titer by 10(4). The RM378 genome consisted of ds DNA of 129.908 bp with a GC ratio of 42.0% and contained about 120 ORFs. A few structural proteins, such as the major head protein corresponding to the gp23 in T4, could be identified. Only 29 gene products as probable homologs to other proteins of known function could be predicted, with most showing only low similarity to known proteins in other bacteriophages. These and other studies based on sequence analysis of a large number of phage genomes showed RM378 to be distantly related to all other known T4-like phages.


Discovering Selective Binders for Photoswitchable Proteins Using Phage Display.
Nature provides an array of proteins that change conformation in response to light. The discovery of a complementary array of proteins that bind only the light-state or dark-state conformation of their photoactive partner proteins would allow each light-switchable protein to be used as an optogenetic tool to control protein-protein interactions. However, as many photoactive proteins have no known binding partner, the advantages of optogenetic control-precise spatial and temporal resolution-are currently restricted to a few well-defined natural systems. In addition, the affinities and kinetics of native interactions are often suboptimal and are difficult to engineer in the absence of any structural information. We report a phage display strategy using a small scaffold protein that can be used to discover new binding partners for both light and dark states of a given light-switchable protein. We used our approach to generate binding partners that interact specifically with the light state or the dark state conformation of two light-switchable proteins: PYP, a test case for a protein with no known partners, and AsLOV2, a well-characterized protein. We show that these novel light-switchable protein-protein interactions can function in living cells to control subcellular localization processes.


High and balanced hole and electron mobilities from ambipolar thin-film transistors based on nitrogen-containing oligoacences.
We demonstrate a strategy for designing high-performance, ambipolar, acene-based field-effect transistor (FET) materials, which is based on the replacement of C-H moieties by nitrogen atoms in oligoacenes. By using this strategy, two organic semiconductors, 6,13-bis(triisopropylsilylethynyl)anthradipyridine (1) and 8,9,10,11-tetrafluoro-6,13-bis(triisopropylsilylethynyl)-1-azapentacene (3), were synthesized and their FET characteristics studied. Both materials exhibit high and balanced hole and electron mobilities, 1 having μ(h) and μ(e) of 0.11 and 0.15 cm(2)/V·s and 3 having μ(h) and μ(e) of 0.08 and 0.09 cm(2)/V·s, respectively. The successful demonstration of high and balanced ambipolar FET properties from nitrogen-containing oligoacenes opens up new opportunities for designing high-performance ambipolar organic semiconductors.


Cost-effectiveness of live oral attenuated human rotavirus vaccine in Tanzania.
Globally, diarrhoea is the second leading cause of morbidity and mortality, responsible for the annual loss of about 10% of the total global childhood disease burden. In Tanzania, Rotavirus infection is the major cause of severe diarrhoea and diarrhoeal mortality in children under five years. Immunisation can reduce the burden, and Tanzania added rotavirus vaccine to its national immunisation programme in January 2013. This study explores the cost effectiveness of introducing rotavirus vaccine within the Tanzania Expanded Programme on Immunisation (EPI). We quantified all health system implementation costs, including programme costs, to calculate the cost effectiveness of adding rotavirus immunisation to EPI and the existing provision of diarrhoea treatment (oral rehydration salts and intravenous fluids) to children. We used ingredients and step down costing methods. Cost and coverage data were collected in 2012 at one urban and one rural district hospital and a health centre in Tanzania. We used Disability Adjusted Life Years (DALYs) as the outcome measure and estimated incremental costs and health outcomes using a Markov transition model with weekly cycles up to a five-year time horizon. The average unit cost per vaccine dose at 93% coverage is US$ 8.4, with marked difference between the urban facility US$ 5.2; and the rural facility US$ 9.8. RV1 vaccine added to current diarrhoea treatment is highly cost effective compared to diarrhoea treatment given alone, with incremental cost effectiveness ratio of US$ 112 per DALY averted, varying from US$ 80-218 in sensitivity analysis. The intervention approaches a 100% probability of being cost effective at a much lower level of willingness-to-pay than the US$609 per capita Tanzania gross domestic product (GDP). The combination of rotavirus immunisation with diarrhoea treatment is likely to be cost effective when willingness to pay for health is higher than USD 112 per DALY. Universal coverage of the vaccine will accelerate progress towards achievement of the child health Millennium Development Goals.


The Personal Doctoring Manifesto: A Perspective from the Keystone IV Conference.
The Keystone IV Conference was a touchstone moment for multigenerational conversations regarding our health care system and an opportunity to reconnect with the values of personal doctoring as a vocation. It inspired participants to renew commitments to relationships, healthy communities, and social change. Keystone IV was also a stark reminder of the need to rekindle family medicine's counterculture flame in today's tumultuous health care environment and reclaim the role of personal doctors in American society. Reimagining and reigniting the fire of personal relationship is today's counterculture movement for primary care. Personal doctors must heed the call for immediate action, which requires defining when relationships matter most in health care and understanding how to harness paradigm shifts in information technology, team-based care, and population health to strengthen, rather than undermine, personal doctoring. Simultaneously, we must also invent a new notion of personal doctoring that creates partnerships with patients and families to drive forward a social movement demanding health care focused on the whole person in the context of his or her community. Change will occur when patients insist on a personal doctoring approach as an essential priority for what they expect from the health care system-that anything less is unacceptable.


Dysmenorrhea in adolescents and young adults: a review in different country.
Dysmenorrhea is still an important public health problem which may have a negative impact on female health, social relationships, school or work activities and psychological status. The aim of this review is a better understanding of the epidemiology of dysmenorrhoea and its effect on public health. Published studies in English providing relevant information on dysmenorrhea were identified by searching PubMed, Embase and Google; restricting the population to adolescents and young adult women and the year of publishing from 2010 to August 2015, based on the keywords 'dysmenorrhea', 'adolescents' and 'epidemiology'. In addition, the reference lists of the selected articles were examined. We found 50 studies that met our inclusion criteria. The majority were cross-sectional studies on 41,140 adolescents and young women published from 2010 onward. The prevalence of dysmenorrhea varied from 34 % (Egypt) to 94% (Oman) and the number of participants, reporting very severe pain varied from 0.9 % (Korea) to 59.8% (Bangladesh). Adolescents who missed school due to dysmenorrhoea ranged from 7.7% to 57.8% and 21.5% missed social activities. About 50% of students (53.7%-47.4%) reported a family history of dysmenorrhea. Incidence of dysmenorrhea was 0.97 times lower as age in-creased (p <0.006). Despite the high prevalence of dysmenorrhea in adolescents, many girls did not receive professional help or treatment. Mothers were the most important persons the girls turned to for answers regarding menstruation, followed by peers (52.9%) and school nurse. From 21% to 96% practised self-medication either by pharmacological or non pharmacological interventions. The limitation of these studies was that they did not distinguish between primary dysmenorrhea and secondary dysmenorrhea. The main gynecological complaint of adolescents is dysmenorrhea. Morbidity due to dysmenorrhea represents a substantial public health burden. It is one of the leading causes of absenteeism from school and work and is responsible for significant diminished quality of life. Despite its high prevalence and associated negative effects, many adolescents do not seek medical care for this condition. Appropriate counselling and management should be instituted among female students to help them cope with the challenges of dysmenorrhea. Information, education and support should also be extended to parents, school peer leaders, and hostel administrators in order to address the reproductive health needs of the female students.


Astronaut Michael Collins, Apollo 8, and the anterior cervical fusion that changed the history of human spaceflight.
In 1961, President John F. Kennedy declared that the United States would send a man to the moon and safely bring him home before the end of the decade. Astronaut Michael Collins was one of those men. He flew to the moon on the historic flight of Apollo 11 while Neil Armstrong and Buzz Aldrin walked on its surface. However, this was not supposed to be the case.Astronaut Collins was scheduled to fly on Apollo 8. While training, in 1968, he started developing symptoms of cervical myelopathy. He underwent evaluation at Wilford Hall Air Force Hospital in San Antonio and was noted to have a C5-6 disc herniation and posterior osteophyte on myelography. Air Force Lieutenant General (Dr.) Paul W. Myers performed an anterior cervical discectomy with placement of iliac bone graft. As a result, Astronaut James Lovell took his place on Apollo 8 flying the uncertain and daring first mission to the moon. This had a cascading effect on the rotation of astronauts, placing Michael Collins on the Apollo 11 flight that first landed men on the moon. It also placed Astronaut James Lovell in a rotation that exposed him to be the Commander of the fateful Apollo 13 flight.Here, the authors chronicle the history of Astronaut Collins' anterior cervical surgery and the impact of his procedure on the rotation of astronaut flight selection, and they review the pivotal historic nature of the Apollo 8 spaceflight. The authors further discuss the ongoing issue of cervical disc herniation among astronauts.


Fatty acid composition modulates sensitivity of Legionella pneumophila to warnericin RK, an antimicrobial peptide.
Warnericin RK is an antimicrobial peptide, produced by a Staphyloccocus warneri strain, described to be specifically active against Legionella, the pathogenic bacteria responsible for Legionnaires' disease. Warnericin RK is an amphiphilic alpha-helical peptide, which possesses a detergent-like mode of action. Two others peptides, δ-hemolysin I and II, produced by the same S. warneri strain, are highly similar to S. aureus δ-hemolysin and also display anti-Legionella activity. It has been recently reported that S. aureus δ-hemolysin activity on vesicles is likewise related to phospholipid acyl-chain structure, such as chain length and saturation. As staphylococcal δ-hemolysins were highly similar, we thus hypothesized that fatty acid composition of Legionella's membrane might influence the sensitivity of the bacteria to warnericin RK. Relationship between sensitivity to the peptide and fatty acid composition was then followed in various conditions. Cells in stationary phase, which were already described as less resistant than cells in exponential phase, displayed higher amounts of branched-chain fatty acids (BCFA) and short chain fatty acids. An adapted strain, able to grow at a concentration 33 fold higher than minimal inhibitory concentration of the wild type (i.e. 1μM), was isolated after repeated transfers of L. pneumophila in the presence of increased concentrations of warnericin RK. The amount of BCFA was significantly higher in the adapted strain than in the wild type strain. Also, a transcriptomic analysis of the wild type and adapted strains showed that two genes involved in fatty acid biosynthesis were repressed in the adapted strain. These genes encode enzymes involved in desaturation and elongation of fatty acids respectively. Their repression was in agreement with the decrease of unsaturated fatty acids and fatty acid chain length in the adapted strain. Conclusively, our results indicate that the increase of BCFA and the decrease of fatty acid chain length in membrane were correlated with the increase in resistance to warnericin RK. Therefore, fatty acid profile seems to play a critical role in the sensitivity of L. pneumophila to warnericin RK.


The evolution of prestige: freely conferred deference as a mechanism for enhancing the benefits of cultural transmission.
This paper advances an "information goods" theory that explains prestige processes as an emergent product of psychological adaptations that evolved to improve the quality of information acquired via cultural transmission. Natural selection favored social learners who could evaluate potential models and copy the most successful among them. In order to improve the fidelity and comprehensiveness of such ranked-biased copying, social learners further evolved dispositions to sycophantically ingratiate themselves with their chosen models, so as to gain close proximity to, and prolonged interaction with, these models. Once common, these dispositions created, at the group level, distributions of deference that new entrants may adaptively exploit to decide who to begin copying. This generated a preference for models who seem generally "popular." Building on social exchange theories, we argue that a wider range of phenomena associated with prestige processes can more plausibly be explained by this simple theory than by others, and we test its predictions with data from throughout the social sciences. In addition, we distinguish carefully between dominance (force or force threat) and prestige (freely conferred deference).


Tumour expression of bladder cancer-associated urinary proteins.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The current basis for diagnosis and prognosis in urinary bladder cancer is based on the pathologists' assessment of a biopsy of the tumour. Urinary biomarkers are preferable as they can be non-invasively sampled. Urinary cytology is the only test with widespread use but is hampered by poor reproducibility and low sensitivity. By studying the protein expression in bladder tumour tissue samples of proteins previously found in elevated levels in the urine of patients with bladder cancer, we have been able to show that these proteins originate from the tumour. The immunoreactivity of three of the investigated proteins increased with higher stage. Also a serine peptidase inhibitor was found to be predictive of progression from non-muscle-invasive to muscle-invasive tumours. To analyse the expression of five bladder cancer-associated urinary proteins and investigate if expression is related to the malignant phenotype of the tumour. To explore the possible prognostic value of these proteins. Urine samples, 16 from patients with bladder cancer and 26 from controls, were used in Western Blotting experiments. Tissue microarrays with bladder tissue from 344 patients diagnosed with bladder cancer between 1984 and 2005 was used in immunohistochemistry experiments. The proteins apolipoprotein E (APOE), fibrinogen β chain precursor (FGB), leucine-rich α2-glycoprotein (LRG1), polymerase (RNA) I polypeptide E (POLR1E), α1-antitrypsin (SERPINA1) and topoisomerase 2A (TOP2A) were probed with antibodies validated by the Human Protein Atlas. Increased expressions of APOE, FGB and POLR1E were correlated with increased tumour stage (P < 0.001). Expression of SERPINA1 in Ta and T1 tumours was found to increase the risk of tumour progression (hazard ratio 2.57, 95% confidence interval 1.13-5.87; P = 0.025) CONCLUSIONS: All proteins previously detected in urine from patients with bladder cancer were also expressed in bladder cancer tissue. The expression of APOE, FGB and POLR1E increased with stage and they are potential diagnostic markers. SERPINA1 was identified as a prognostic marker candidate.


Optimal electromagnetic energy transmission and real-time dissipation in extended media.
Pulse reshaping effects that give rise to fast and slow light phenomena are inextricably linked to the dynamics of energy exchange between the pulse and the propagation medium. Energy that is dissipated from the pulse can no longer participate in this exchange process, but previous methods of calculating real-time dissipation are not valid for extended propagation media. We present a method for calculating real-time dissipation that is valid for electromagnetic pulse propagation in extended media. This method allows one to divide the energy stored in an extended medium into the portion that can be later transmitted out of the medium, and that portion which must be lost to either dissipation or reflection.


The role of workplace low-level mechanical trauma, posture and environment in the onset of chronic widespread pain.
We have recently demonstrated that individual psychosocial factors are important predictors of the onset of chronic widespread pain. It has been hypothesized that excessive mechanical exposure may also be associated with symptom onset, although this has not been formally examined. We therefore determined the relative contributions of individual psychosocial and work-related mechanical, posture and environment factors in symptom onset. We conducted a population-based prospective survey and identified 1658 adults aged 18-65 yr who were symptom-free. At baseline, detailed information was obtained on work-related mechanical and environment factors using validated instruments. Individual psychosocial features were also measured. Subjects free of chronic widespread pain at baseline were followed up at 12 and 36 months to identify those reporting the onset of new symptoms. In all, 1445 (91%) returned the questionnaire at 12 months and 978 (89%) at 36 months. Of these, 81 and 92 respectively reported new chronic widespread pain. Symptom onset was predicted by workplace factors [pushing/pulling heavy weights [relative risk (RR) = 1.8, 95% confidence interval (CI) 1.1, 3.0]; repetitive movements of the wrists (RR = 1.8, 95% CI 1.2, 2.7); kneeling (RR = 2.2, 95% CI 1.2, 4.1)] and individual factors [aspects of illness behaviour (RR = 2.9, 95% CI 1.6, 5.3); somatic symptoms (RR = 1.9 95% CI 1.1, 3.3); fatigue (RR = 1.9, 95% CI 1.2, 3.1); baseline pain symptoms (RR = 2.5, 95% CI 1.6, 3.9)]. In multivariate analysis, pushing/pulling heavy weights, repetitive wrist movements, kneeling and other pain at baseline were associated with new-onset chronic widespread pain. However, the strongest predictor was a high score on the illness behaviour scale. This study provides only limited support for the hypothesis that low-level mechanical injury may be a risk factor for developing chronic widespread pain. The onset of chronic widespread pain appears to be multifactorial and is strongly predicted by individual psychosocial factors.


Systematic Discovery of Human Gene Function and Principles of Modular Organization through Phylogenetic Profiling.
Functional links between genes can be predicted using phylogenetic profiling, by correlating the appearance and loss of homologs in subsets of species. However, effective genome-wide phylogenetic profiling has been hindered by the large fraction of human genes related to each other through historical duplication events. Here, we overcame this challenge by automatically profiling over 30,000 groups of homologous human genes (orthogroups) representing the entire protein-coding genome across 177 eukaryotic species (hOP profiles). By generating a full pairwise orthogroup phylogenetic co-occurrence matrix, we derive unbiased genome-wide predictions of functional modules (hOP modules). Our approach predicts functions for hundreds of poorly characterized genes. The results suggest evolutionary constraints that lead components of protein complexes and metabolic pathways to co-evolve while genes in signaling and transcriptional networks do not. As a proof of principle, we validated two subsets of candidates experimentally for their predicted link to the actin-nucleating WASH complex and cilia/basal body function.


First Report of Pilidiella granati Causing Dieback and Fruit Rot of Pomegranate (Punica granatum) in Iran.
Iran is the largest producer of pomegranate (Punica granatum) in the world, with more than 60,000 ha currently in production. In the spring of 2011, a decline and dieback of young pomegranate trees (7 to 10 years old) were observed in the Kheir area of Fars Province. Dieback and twig blight developed toward the lower part of the stem, resulting in death of aerial tree parts and growing suckers from roots. Surface-disinfected tissues of diseased plants were plated on potato dextrose agar (PDA) and malt extract agar media. Isolates were separated into two groups that had either pale green or white aerial mycelia and sporulated after 5 to 7 days at 25°C. Pycnidia were globose and black with thin, membranous, pseudoparenchymatic walls, 80 to 140 μm in diameter. Conidia were hyaline, one-celled, elongate to fusiform, straight, and 11 to 17 × 4 to 6 μm (average 14 × 4.7 μm). Cardinal minimum growth temperatures were 8 to 10°C, optimum at 27 to 30°C, and maximum at 35°C. Radial growth rate at 30°C was 8 to 9 mm per day. Representative isolates were deposited in the CBS-KNAW Fungal Biodiversity Centre, the Netherlands (CPC 19625 = CBS 130974 and CPC 19626 = CBS 130975; GenBank JN815312 and JN815313, respectively). Genomic DNA was extracted with the UltraClean Microbial DNA Isolation Kit (MoBio Laboratories, Inc., Solana Beach, CA) and the internal transcribed spacer (ITS) region of the nrDNA operon of two isolates were sequenced as described previously (1). On the basis of morphology (3), the causal organism was identified as Pilidiella granati Sacc. This identification was corroborated by the ITS sequence data, which was identical for both colony types to GenBank HQ166057 (identities = 614 of 614 [100%]). Pathogenicity tests were conducted using two representative isolates from each group on 5-month-old P. granatum trees with 10 replicates under greenhouse conditions; 5-mm mycelial plugs from the edge of 7-day-old colonies on PDA were placed under the bark of twig wounds. Uncolonized PDA plugs were used as noninoculated controls. Pathogenicity was also tested on nonwounded fruit by placing colonized 5-mm-diameter mycelial plugs on surface-disinfected pomegranate fruits; noncolonized PDA plugs were used as controls. All treated fruit were placed in plastic bags and maintained at 25°C for 10 days. Isolates were found to be pathogenic on twigs after 2 months, giving rise to brown lesions that were 2 to 5 cm long. No lesions were observed on the controls. Furthermore, the fungus was reisolated from all infected tissues, satisfying Koch's postulates. On pomegranate fruit, the fungus colonized the fruit after 5 to 8 days, followed by the appearance of fruit rot symptoms leading to the formation of abundant pycnidia covering the skin after 10 days. No decay was observed in control inoculations. Pilidiella granati has previously been reported as a pathogen of P. granatum fruit from Europe, Asia, and the United States (2). To our knowledge, this is the first report of this pathogen causing dieback and fruit rot of pomegranate in Iran. References: (1) J. Frank et al. Persoonia 24:93, 2010. (2) L. Palou et al. Online publication. doi:10.5197/j.2044.0588.2010.022.021. New Dis. Rep. 22:21, 2010. (3) J. M. Van Niekerk et al. Mycol. Res. 108:283, 2004.


Communication and cognitive impairments and health care decision making in MND: A narrative review.
Motor neurone disease (MND) is a neurodegenerative disease presenting with progressive weakness of voluntary muscles. For any condition, person-centred health care relies on the sharing of information and a mutual understanding of the person's needs and preferences. Decision making in MND becomes more complex as there is no cure and a high prevalence of co-morbid communication and/or cognitive difficulties. To identify the reported impact of communication and/or cognitive impairment on patient and carer involvement in health care decision making in MND. A review and synthesis of studies addressing issues of communication impairment and/or cognitive impairment in relation to decision making focussed on MND was conducted. Articles were excluded if they were reviews, case studies, conference papers, or commentaries. To be included studies needed to address issues of communication impairment or cognitive impairment specifically in relation to decision making. Relevant data were extracted verbatim and subjected to content analysis to support the narrative summary. Seventy-six articles were identified, and 35 articles screened. Six articles met inclusion criteria each describing examples of decision making in MND. There was limited data related to communication and/or cognitive impairment, and the impact these impairments may have on decision making despite recognition that many people with MND may lose verbal communication or develop subtle cognitive impairments. The literature is primarily from the perspective of others. This review highlights that the current body of literature exploring decision making within the MND population presents us with extremely limited insights into the impact of communication and/or cognitive impairments on health care decision making. Extant literature focuses on interventions (namely, ventilation and gastrostomy), the broad process of decision making, or cognitive assessment of decision-making ability. Whilst most studies acknowledge that deficits in communication or cognition impact the decision-making process, this issue is not the focus of any study.


Individual variation in cone photoreceptor density in house sparrows: implications for between-individual differences in visual resolution and chromatic contrast.
Between-individual variation has been documented in a wide variety of taxa, especially for behavioral characteristics; however, intra-population variation in sensory systems has not received similar attention in wild animals. We measured a key trait of the visual system, the density of retinal cone photoreceptors, in a wild population of house sparrows (Passer domesticus). We tested whether individuals differed from each other in cone densities given within-individual variation across the retina and across eyes. We further tested whether the existing variation could lead to individual differences in two aspects of perception: visual resolution and chromatic contrast. We found consistent between-individual variation in the densities of all five types of avian cones, involved in chromatic and achromatic vision. Using perceptual modeling, we found that this degree of variation translated into significant between-individual differences in visual resolution and the chromatic contrast of a plumage signal that has been associated with mate choice and agonistic interactions. However, there was no evidence for a relationship between individual visual resolution and chromatic contrast. The implication is that some birds may have the sensory potential to perform "better" in certain visual tasks, but not necessarily in both resolution and contrast simultaneously. Overall, our findings (a) highlight the need to consider multiple individuals when characterizing sensory traits of a species, and (b) provide some mechanistic basis for between-individual variation in different behaviors (i.e., animal personalities) and for testing the predictions of several widely accepted hypotheses (e.g., honest signaling).


Ingested insecticide to control Aedes aegypti: developing a novel dried attractive toxic sugar bait device for intra-domiciliary control.
Illnesses transmitted by Aedes aegypti (Linnaeus, 1762) such as dengue, chikungunya and Zika comprise a considerable global burden; mosquito control is the primary public health tool to reduce disease transmission. Current interventions are inadequate and insecticide resistance threatens the effectiveness of these options. Dried attractive bait stations (DABS) are a novel mechanism to deliver insecticide to Ae. aegypti. The DABS are a high-contrast 28 inch2 surface coated with dried sugar-boric acid solution. Aedes aegypti are attracted to DABS by visual cues only, and the dried sugar solution elicits an ingestion response from Ae. aegypti landing on the surface. The study presents the development of the DABS and tests of their impact on Ae. aegypti mortality in the laboratory and a series of semi-field trials. We conducted multiple series of laboratory and semi-field trials to assess the survivability of Ae. aegypti mosquitoes exposed to the DABS. In the laboratory experiments, we assessed the lethality, the killing mechanism, and the shelf life of the device through controlled experiments. In the semi-field trials, we released laboratory-reared female Ae. aegypti into experimental houses typical of peri-urban tropical communities in South America in three trial series with six replicates each. Laboratory experiments were conducted in Quito, Ecuador, and semi-field experiments were conducted in Machala, Ecuador, an area with abundant wild populations of Ae. aegypti and endemic arboviral transmission. In the laboratory, complete lethality was observed after 48 hours regardless of physiological status of the mosquito. The killing mechanism was determined to be through ingestion, as the boric acid disrupted the gut of the mosquito. In experimental houses, total mosquito mortality was greater in the treatment house for all series of experiments (P < 0.0001). The DABS devices were effective at killing female Ae. aegypti under a variety of laboratory and semi-field conditions. DABS are a promising intervention for interdomiciliary control of Ae. aegypti and arboviral disease prevention.


Treating 'AIDS blindness': a critical pedagogical approach to HIV education at tertiary level.
HIV and AIDS affect all South Africans, irrespective of gender, race, age and economic status. Teachers should therefore be able to meaningfully integrate HIV content into the school curriculum. However, pre-service teacher education programmes still do not pay adequate attention to HIV education, particularly in institutions where students are being prepared to work in environments that are perceived to be unaffected by the consequences of the pandemic. This article advocates that HIV education should be integrated into contexts of privilege and presents evidence of the influence that a critical pedagogical approach can have on changing student perceptions of the need to address HIV in and through their teaching. We led 109 Post-graduate Certificate of Education students through a series of activities that required them to critically reflect on their feelings, attitudes and perceived skills with regard to HIV and AIDS education; to identify potential areas of personal change; and to begin to imagine alternative professional possibilities. We generated qualitative data through drawings, group discussions, individual written reflections, and a voluntary focus group. A content analysis of the data revealed that the participating students initially felt incompetent to incorporate HIV and related issues into their teaching, and felt hesitant and uncomfortable at the prospect. However, a critical reflection on their thinking, both individually and in a group setting, served to shift them towards a more holistic, critical and humanising understanding of the pandemic and the role they could play as future teachers in helping to mitigate its impact. The findings provide evidence that a critical pedagogical approach - particularly with groups who believe that HIV and AIDS is not something that concerns them - can provide an effective way to mediate the knowledge, skills and attitudes that competent teachers need in today's world.


Mice lacking both presenilin genes exhibit early embryonic patterning defects.
Genetic studies in worms, flies, and humans have implicated the presenilins in the regulation of the Notch signaling pathway and in the pathogenesis of Alzheimer's Disease. There are two highly homologous presenilin genes in mammals, presenilin 1 (PS1) and presenilin 2 (PS2). In mice, inactivation of PS1 leads to developmental defects that culminate in a perinatal lethality. To test the possibility that the late lethality of PS1-null mice reflects genetic redundancy of the presenilins, we have generated PS2-null mice by gene targeting, and subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted null mutation in PS2 exhibit no obvious defects; however, loss of PS2 on a PS1-null background leads to embryonic lethality at embryonic day 9.5. Embryos lacking both presenilins, and surprisingly, those carrying only a single copy of PS2 on a PS1-null background, exhibit multiple early patterning defects, including lack of somite segmentation, disorganization of the trunk ventral neural tube, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development. In addition, Delta like-1 (Dll1) and Hes-5, two genes that lie downstream in the Notch pathway, were misexpressed in presenilin double-null embryos: Hes-5 expression was undetectable in these mice, whereas Dll1 was expressed ectopically in the neural tube and brain of double-null embryos. We conclude that the presenilins play a widespread role in embryogenesis, that there is a functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling.


Dopaminergic regulation of natriuretic response to acute volume expansion in dogs.
Effects of carbidopa, a dopa (3,4-dihydroxyphenylamine) decarboxylase inhibitor, on the renal, haemodynamic and hormonal responses to acute volume expansion were examined in six healthy mongrel dogs which were infused intravenously with 0.9% sodium chloride solution (saline; 30 ml h-1 kg-1) over 2 h. Saline infusion studies were performed in the absence (control) and in the presence of carbidopa given by nasogastric tube in a dose of 1 mg/kg every 8 h beginning 24 h before the infusion. Saline infusion resulted in an increase in renal excretion of dopamine (3,4-dihydroxyphenylethylamine) and a decrease in renal excretion of noradrenaline. Carbidopa treatment decreased urinary sodium excretion and eliminated the increase in renal production of dopamine in response to saline infusion without affecting renal or haemodynamic response to acute vascular volume expansion with saline. Carbidopa treatment obliterated the suppression of aldosterone produced by saline infusion. Thus, dopamine appears to play a significant role in mediating both the natriuretic and aldosterone response to acute volume expansion.


Genomic analysis of codon usage shows influence of mutation pressure, natural selection, and host features on Marburg virus evolution.
The Marburg virus (MARV) has a negative-sense single-stranded RNA genome, belongs to the family Filoviridae, and is responsible for several outbreaks of highly fatal hemorrhagic fever. Codon usage patterns of viruses reflect a series of evolutionary changes that enable viruses to shape their survival rates and fitness toward the external environment and, most importantly, their hosts. To understand the evolution of MARV at the codon level, we report a comprehensive analysis of synonymous codon usage patterns in MARV genomes. Multiple codon analysis approaches and statistical methods were performed to determine overall codon usage patterns, biases in codon usage, and influence of various factors, including mutation pressure, natural selection, and its two hosts, Homo sapiens and Rousettus aegyptiacus. Nucleotide composition and relative synonymous codon usage (RSCU) analysis revealed that MARV shows mutation bias and prefers U- and A-ended codons to code amino acids. Effective number of codons analysis indicated that overall codon usage among MARV genomes is slightly biased. The Parity Rule 2 plot analysis showed that GC and AU nucleotides were not used proportionally which accounts for the presence of natural selection. Codon usage patterns of MARV were also found to be influenced by its hosts. This indicates that MARV have evolved codon usage patterns that are specific to both of its hosts. Moreover, selection pressure from R. aegyptiacus on the MARV RSCU patterns was found to be dominant compared with that from H. sapiens. Overall, mutation pressure was found to be the most important and dominant force that shapes codon usage patterns in MARV. To our knowledge, this is the first detailed codon usage analysis of MARV and extends our understanding of the mechanisms that contribute to codon usage and evolution of MARV.


Altered phenotype and Stat1 expression in Toll-like receptor 7/8 stimulated monocyte-derived dendritic cells from patients with primary Sjögren's syndrome.
Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system, involved in both initiating immune responses and maintaining tolerance. Dysfunctional and via toll-like receptor (TLR) ligands activated DC have been implicated in the development of autoimmune diseases, but their role in the etiology of Sjögren's syndrome, a chronic inflammatory autoimmune disease characterized by progressive mononuclear cell infiltration in the exocrine glands, has not been revealed yet. Therefore, the aim of this study was to investigate phenotype and functional properties of immature and TLR7/8 stimulated monocyte-derived DC (moDC) of patients with primary Sjögren's syndrome (pSS) and compare them to healthy controls. The phenotype, apoptosis susceptibility and endocytic capacity of moDC were analyzed by flow cytometry. Secretion of cytokines was measured by enzyme-linked immunosorbent assay (ELISA) and multiplex Luminex analyses in moDC cell culture supernatants. The expression of TLR7 was analyzed by flow cytometry and real-time quantitative polymerase chain reaction (qPCR). Expression of Ro/Sjögren's syndrome-associated autoantigen A (Ro52/SSA), interferon regulatory factor 8 (IRF-8), Bim, signal transduction and activators of transcription (Stat) 1, p-Stat1 (Tyrosin 701), p-Stat1 (Serin 727), Stat3, pStat3 (Tyrosin 705) and glyceraldehyde 3-phosphatase dehydrogenase (GAPDH) was measured by Western blotting. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family members were quantified using the ELISA-based TransAM NF-κB family kit. We could not detect differences in expression of co-stimulatory molecules and maturation markers such as cluster of differentiation (CD) 86, CD80, CD40 or CD83 on moDC from patients compared to healthy controls. Moreover, we could not observe variations in apoptosis susceptibility, Bim and Ro52/SSA expression and the endocytic capacity of the moDC. However, we found that moDC from pSS patients expressed increased levels of the major histocompatibility complex (MHC) class II molecule human leukocyte antigen (HLA)-DR. We also found significant differences in cytokine production by moDC, where increased interleukin (IL)-12p40 secretion in mature pSS moDC correlated with increased RelB expression. Strikingly, moDC from pSS patients matured for 48 hours with TLR7/8 ligand CL097 expressed significantly less Stat1. Our results suggest a role for moDC in the pathogenesis of Sjögren's syndrome.


ARS2 is a conserved eukaryotic gene essential for early mammalian development.
Determining the functions of novel genes implicated in cell survival is directly relevant to our understanding of mammalian development and carcinogenesis. ARS2 is an evolutionarily conserved gene that confers arsenite resistance on arsenite-sensitive Chinese hamster ovary cells. Little is known regarding the function of ARS2 in mammals. We report that ARS2 is transcribed throughout embryonic development and is expressed ubiquitously in mouse and human tissues. The mouse ARS2 protein is predominantly localized to the nucleus, and this nuclear localization is ablated in ARS2-null embryos, which in turn die around the time of implantation. After 24 h of culture, ARS2-null blastocysts contained a significantly greater number of apoptotic cells than wild-type or heterozygous blastocysts. By 48 h of in vitro culture, null blastocysts invariably collapsed and failed to proliferate. These data indicate ARS2 is essential for early mammalian development and is likely involved in an essential cellular process. The analysis of data from several independent protein-protein interaction studies in mammals, combined with functional studies of its Arabidopsis ortholog, SERRATE, suggests that this essential process is related to RNA metabolism.


A unified framework for association and prediction from vertex-wise grey-matter structure.
The recent availability of large-scale neuroimaging cohorts facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. Here, we investigate the association (previously coined morphometricity) of a phenotype with all 652,283 vertex-wise measures of cortical and subcortical morphology in a large data set from the UK Biobank (UKB; N = 9,497 for discovery, N = 4,323 for replication) and the Human Connectome Project (N = 1,110). We used a linear mixed model with the brain measures of individuals fitted as random effects with covariance relationships estimated from the imaging data. We tested 167 behavioural, cognitive, psychiatric or lifestyle phenotypes and found significant morphometricity for 58 phenotypes (spanning substance use, blood assay results, education or income level, diet, depression, and cognition domains), 23 of which replicated in the UKB replication set or the HCP. We then extended the model for a bivariate analysis to estimate grey-matter correlation between phenotypes, which revealed that body size (i.e., height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the morphometricity (confirmed using a conditional analysis), providing possible insight into previous MRI case-control results for psychiatric disorders where case status is associated with body mass index. Our LMM framework also allowed to predict some of the associated phenotypes from the vertex-wise measures, in two independent samples. Finally, we demonstrated additional new applications of our approach (a) region of interest (ROI) analysis that retain the vertex-wise complexity; (b) comparison of the information retained by different MRI processings.


In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function.
The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac beta-adrenergic receptor (betaAR) system, which is critical in the regulation of myocardial function. Expression of the betaAR kinase (betaARK1), which phosphorylates and uncouples betaARs, is elevated in human HF; this likely contributes to the abnormal betaAR responsiveness that occurs with beta-agonist administration. We previously showed that transgenic mice with increased myocardial betaARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous betaARK1 activity in the heart led to enhanced myocardial function. We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both betaARK1 and an inhibitor of betaARK1 activity to study the feasibility and functional consequences of the inhibition of elevated betaARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of betaARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial betaARK1 levels remained elevated due to transgene expression, in vitro betaARK1 activity returned to control levels and the percentage of betaARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to betaAR stimulation was restored to normal in the hybrid double-transgenic mice. Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial betaARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac betaARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.


An integrated process for enzymatic catalysis allowing product recovery and enzyme reuse by applying thermoreversible aqueous biphasic systems.
Thermoreversible aqueous biphasic systems (ABS) composed of ammonium-based zwitterions (ZIs) and polymers are here disclosed to act as integrated bioreaction-separation processes. The biocatalytic reaction involving laccase occurs in homogeneous media, after which small changes in temperature induce the formation of two phases and the complete separation of the enzyme from the products in a single-step. These systems also allow the recover and reuse of the enzyme, along with the ZI-rich phase, contributing towards the development of sustainable biocatalytic processes.


Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review.
Attention-deficit/hyperactivity disorder (ADHD) is characterised by a persistent and impairing pattern of inattention and/or hyperactivity/impulsivity and it is one of the most common neuropsychiatric conditions. Evidence about interventions of adults with ADHD is growing rapidly and clinicians need a reliable summary of all the best available information in order to better inform their daily practice. We searched MEDLINE, PubMed, PsycINFO and Cochrane databases until 31 May 2016 for systematic reviews about pharmacological and non-pharmacological treatments in adults with ADHD and carried out a meta-review to address clinically relevant questions. We identified a total of 40 papers. Psychostimulants-such as methylphenidate, dexamphetamine, mixed amphetamine salts and lisdexamfetamine-and non-psychostimulants-such as atomoxetine-were the most studied agents. Overall, pharmacological treatments were significantly more efficacious than placebo (standardised mean difference (SMD) 0.45, 95% CI 0.37 to 0.52), albeit less well accepted (OR 1.18, 95% CI 1.02 to 1.36) and tolerated (OR 2.29, 95% CI 1.97 to 2.66). The effects of pharmacological treatment for individuals with co-occurring ADHD and substance use disorder are still uncertain. The evidence for the efficacy and effectiveness of non-pharmacological treatments of ADHD in adults, as well as the combination of pharmacological and non-pharmacological strategies, is only preliminary. In conclusion, while available evidence addressed mainly the efficacy and tolerability of psychostimulants and non-psychostimulants for ADHD core symptoms in the short term, we still need further empirical support for the non-pharmacological and multimodal treatments. A comprehensive evidence-informed hierarchy of ADHD drugs based on their efficacy and tolerability is not yet available but it should be the next research priority in the field.


Excitatory and inhibitory motor reflexes in the isolated guinea-pig stomach.
1. We have described and analysed the movements of the isolated stomach during distension by correlating intragastric pressure with video recordings, and investigated the presence of intrinsic inhibitory and excitatory reflexes. 2. Isolated guinea-pig stomachs, placed in an organ bath, were slowly distended with Krebs solution using a syringe pump via a cannula through the pylorus. The changes in intragastric pressure during cycles of distension were monitored by pressure transducers connected to both oesophageal and pyloric cannulae. The resistivity of the gastric wall (change in pressure with volume, delta P/delta V) and the amplitude and frequency of phasic pressure events were calculated from pressure recordings. 3. The movements of the stomach were also recorded onto videotape. The motion of the gastric wall during distension cycles was analysed to establish the patterns of contractions, their propagation and the distribution of fluid in the stomach. During filling, fluid was preferentially accommodated in the fundus. Propagating (peristaltic) contractions, often starting in the fundus, moved aborally towards the pylorus. The peak of the phasic pressure event was observed when a contraction reached the orad antrum. As it reached the pylorus, intragastric pressure was at its minimum. 4. During the initial phase of distension, intragastric pressure increased steeply. Tetrodotoxin and hyoscine reduced both the resistivity and amplitude of phasic pressure events. Hexamethonium had a similar effect. Thus distension appears to activate an excitatory reflex pathway, involving nicotinic ganglionic transmission. This reflex increases wall tension and enhances myogenic peristaltic contractions. 5. In control preparations, with larger distension volumes, the intragastric pressure decreased, despite the continued infusion of Krebs solution. L-NAME and apamin abolished this drop in pressure, indicating that gastric enteric inhibitory mechanisms prevail at larger distension volumes. After blockade of the excitatory reflex, hexamethonium antagonized the inhibitory response, indicating that activation of inhibitory mechanisms involves nicotinic transmission, probably on enteric inhibitory motoneurons. 6. Both the excitatory and inhibitory reflexes in the isolated stomach operate within a physiological range of gastric volumes. The excitatory reflex predominates at small distension volumes, leading to large phasic propagated contractions that mix the contents and may lead to emptying of the stomach. The inhibitory reflex, described previously as adaptive relaxation, can maximally relax the stomach and is activated preferentially at higher distension volumes to accommodate the contents. The interplay of these reflex pathways in the isolated stomach produces a rich repertoire of gastric movements. 7. The isolated stomach preparation, used with a combination of kinematic, kinetic and pharmacological methods, provides a highly suitable means of investigating the mechanisms of gastric motility.


Evaluation of magnifying colonoscopy in the diagnosis of serrated polyps.
To elucidate the colonoscopic features of serrated lesions of the colorectum using magnifying colonoscopy. Broad division of serrated lesions of the colorectum into hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), and sessile serrated adenomas/polyps (SSA/Ps) has been proposed on the basis of recent molecular biological studies. However, few reports have examined the colonoscopic features of these divisions, including magnified colonoscopic findings. This study examined 118 lesions excised in our hospital as suspected serrated lesions after magnified observation between January 2008 and September 2011. Patient characteristics (sex, age), conventional colonoscopic findings (location, size, morphology, color, mucin) and magnified colonoscopic findings (pit pattern diagnosis) were interpreted by five colonoscopists with experience in over 1000 colonoscopies, and were compared with histopathological diagnoses. The pit patterns were categorized according to Kudo's classification, but a more detailed investigation was also performed using the subclassification [type II-Open (type II-O), type II-Long (type II-L), or type IV-Serrated (type IV-S)] proposed by Kimura T and Yamano H. Lesions comprised 23 HPs (23/118: 19.5%), 39 TSAs (39/118: 33.1%: with cancer in one case), 50 SSA/Ps (50/118: 42.4%: complicated with cancer in three cases), and six others (6/118: 5.1%). We excluded six others, including three regular adenomas, one hamartoma, one inflammatory polyp, and one juvenile polyp for further analysis. Conventional colonoscopy showed that SSA/Ps were characterized as larger in diameter than TSAs and HPs (SSA/P vs HP, 13.62 ± 8.62 mm vs 7.74 ± 3.24 mm, P < 0.001; SSA/Ps vs TSA, 13.62 ± 8.62 mm vs 9.89 ± 5.73 mm, P < 0.01); common in the right side of the colon [HPs, 30.4% (7/23): TSAs, 20.5% (8/39): SSA/P, 84.0% (42/50), P < 0.001]; flat-elevated lesion [HPs, 30.4% (7/23): TSAs, 5.1% (2/39): SSA/Ps, 90.0% (45/50), P < 0.001]; normal-colored or pale imucosa [HPs, 34.8% (8/23): TSAs, 10.3% (4/39): SSA/Ps, 80% (40/50), P < 0.001]; and with large amounts of mucin [HPs, 21.7% (5/23): TSAs, 17.9% (7/39): SSA/Ps, 72.0% (36/50), P < 0.001]. In magnified colonoscopic findings, 17 lesions showed either type II pit pattern alone or partial type II pit pattern as the basic architecture, with 14 HPs (14/17, 70.0%) and 3 SSA/Ps. Magnified colonoscopy showed the type II-O pit pattern as characteristic of SSA/Ps [sensitivity 83.7% (41/49), specificity 85.7% (54/63)]. Cancer was also present in three lesions, in all of which a type VI pit pattern was also present within the same lesion. There were four HPs and four TSAs each. The type IV-S pit pattern was characteristic of TSAs [sensitivity 96.7% (30/31), specificity 89.9% (72/81)]. Cancer was present in one lesion, in which a type VI pit pattern was also present within the same lesion. In our study, serrated lesions of the colorectum also possessed the features described in previous reports of conventional colonoscopic findings. The pit pattern diagnosis using magnifying colonoscopy, particularly magnified colonoscopic findings using subclassifications of surface architecture, reflected the pathological characteristics of SSA/Ps and TSAs, and will be useful for colonoscopic diagnosis. We suggest that this system could be a good diagnostic tool for SSA/Ps using magnifying colonoscopy.


[Prevalence, persistency and consequences of ADHD in the Dutch adult population].
Little is known about the prevalence and the consequences of attention-deficit hyperactivity disorder (ADHD) among adults in the general Dutch population. To ascertain the prevalence of ADHD in childhood and adulthood, to investigate characteristics associated with the prevalence and persistency of ADHD and to draw a number of comparisons: to compare the functioning of adults with ADHD with that of people with a different mental disorder and to compare the extent to which these groups make use of treatment facilities. Data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), in which the occurrence of ADHD was determined in a representative sample of the Dutch population (n = 3,309; aged 18-44). 2.9% of the respondents had had ADHD in childhood, 70.0% of them still had the disorder in adulthood. An anxiety disorder before the age of 16 increased the risk of ADHD persistency, whereas an impulse-control disorder decreased this risk. ADHD in adulthood was associated with lower socio-economic status, mental disorders, poor functioning and increased use of treatment facilities. ADHD adults and adults with an anxiety or substance use disorder showed very similar functional limitations and used treatment facilities to approximately the same extent. More than two-thirds of the adults who had had childhood ADHD still had the disorder in adulthood. The consequences of this in terms of functioning and use of treatment facilities are substantial.


Development of an individual-based model for polioviruses: implications of the selection of network type and outcome metrics.
We developed an individual-based (IB) model to explore the stochastic attributes of state transitions, the heterogeneity of the individual interactions, and the impact of different network structure choices on the poliovirus transmission process in the context of understanding the dynamics of outbreaks. We used a previously published differential equation-based model to develop the IB model and inputs. To explore the impact of different types of networks, we implemented a total of 26 variations of six different network structures in the IB model. We found that the choice of network structure plays a critical role in the model estimates of cases and the dynamics of outbreaks. This study provides insights about the potential use of an IB model to support policy analyses related to managing the risks of polioviruses and shows the importance of assumptions about network structure.


Phytochemical, pharmacological and toxicological aspects of Hibiscus sabdariffa L.: a review.
This article reviews the reported phytochemical, pharmacological and toxicological properties of Hibiscus sabdariffa L. (English: roselle, red sorrel; Arabic: karkade), the calyces of which are used in many parts of the world to make cold and hot drinks. Nutritionally, these contain ascorbic acid (vitamin C). In folk medicine, the calyx extracts are used for the treatment of several complaints, including high blood pressure, liver diseases and fever. The pharmacological actions of the calyx extracts include strong in vitro and in vivo antioxidant activity. In rats and rabbits, the extract showed antihypercholesterolaemic, antinociceptive and antipyretic, but not antiinflammatory activities. In rat and man a strong antihypertensive action has been demonstrated. The effects of the calyx extracts on smooth muscles in vitro are variable, but they mostly inhibit the tone of the isolated muscles. In healthy men, consumption of H. sabdariffa has resulted in significant decreases in the urinary concentrations of creatinine, uric acid, citrate, tartrate, calcium, sodium, potassium and phosphate, but not oxalate. Oil extracted from the plant's seeds has been shown to have an inhibitory effect on some bacteria and fungi in vitro. The plant extracts are characterized by a very low degree of toxicity. The LD50 of H. sabdariffa calyx extract in rats was found to be above 5000 mg/kg. A single report has suggested that excessive doses for relatively long periods could have a deleterious effect on the testes of rats. In view of its reported nutritional and pharmacological properties and relative safety, H. sabdariffa and compounds isolated from it (for example, anthocyanins and Hibiscus protocatechuic acid) could be a source of therapeutically useful products.


Consonance and dissonance of musical chords: neural correlates in auditory cortex of monkeys and humans.
Some musical chords sound pleasant, or consonant, while others sound unpleasant, or dissonant. Helmholtz's psychoacoustic theory of consonance and dissonance attributes the perception of dissonance to the sensation of "beats" and "roughness" caused by interactions in the auditory periphery between adjacent partials of complex tones comprising a musical chord. Conversely, consonance is characterized by the relative absence of beats and roughness. Physiological studies in monkeys suggest that roughness may be represented in primary auditory cortex (A1) by oscillatory neuronal ensemble responses phase-locked to the amplitude-modulated temporal envelope of complex sounds. However, it remains unknown whether phase-locked responses also underlie the representation of dissonance in auditory cortex. In the present study, responses evoked by musical chords with varying degrees of consonance and dissonance were recorded in A1 of awake macaques and evaluated using auditory-evoked potential (AEP), multiunit activity (MUA), and current-source density (CSD) techniques. In parallel studies, intracranial AEPs evoked by the same musical chords were recorded directly from the auditory cortex of two human subjects undergoing surgical evaluation for medically intractable epilepsy. Chords were composed of two simultaneous harmonic complex tones. The magnitude of oscillatory phase-locked activity in A1 of the monkey correlates with the perceived dissonance of the musical chords. Responses evoked by dissonant chords, such as minor and major seconds, display oscillations phase-locked to the predicted difference frequencies, whereas responses evoked by consonant chords, such as octaves and perfect fifths, display little or no phase-locked activity. AEPs recorded in Heschl's gyrus display strikingly similar oscillatory patterns to those observed in monkey A1, with dissonant chords eliciting greater phase-locked activity than consonant chords. In contrast to recordings in Heschl's gyrus, AEPs recorded in the planum temporale do not display significant phase-locked activity, suggesting functional differentiation of auditory cortical regions in humans. These findings support the relevance of synchronous phase-locked neural ensemble activity in A1 for the physiological representation of sensory dissonance in humans and highlight the merits of complementary monkey/human studies in the investigation of neural substrates underlying auditory perception.


The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.


Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology.
Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions.


Reliability of isometric strength testing. Temporal factors and strength variation.
Isometric strength measurements of grip, pronation, supination, and elbow extension and flexion on dominant and nondominant sides were made on 40 normal subjects (age range, 40-70 years) to investigate the variability of isometric strength at different times of the day. Statistically significant differences were found in certain pronation, supination, and grip comparisons. No statistically significant difference was found in extension and flexion. Although significant, the absolute change in strength at different times of the day was small and showed no consistent trend. On the basis of these data, it appears that this variation can probably not be routinely detected in the normal clinical setting. However, the study further defines the reliability of isometric strength testing and should be considered in further attempts at more accurate measurement of elbow function. The small variations of strength, approximately 5%, that can be measured universally with sensitive testing equipment, are clinically relevant. However, when attempting to determine an impairment state in order not to place too much importance on small differences, care should be exercised in interpreting strength measurements. This investigation demonstrates how the application of sophisticated biomechanical techniques may be employed to provide useful objective information in the difficult clinical area of disability assessment. Disability judgments may be made more accurate as more is learned of the normal variables influencing objective measurement.


Interaction of ofloxacin with organic cation transport system in rat renal brush-border membranes.
Ofloxacin, a pyridonecarboxylic acid derivative, was examined for its effects on the transport of tetraethylammonium (cation), cephalexin and cephradine (zwitterions), p-aminohippurate (anion) and D-glucose in brush-border membrane vesicles isolated from rat renal cortex. The initial uptake of tetraethylammonium in the presence or absence of an outward H+ gradient was inhibited by ofloxacin in a dose-dependent manner, although the equilibrium value of tetraethylammonium uptake was not affected. This inhibition occurred in a competitive manner (Ki = 0.11 mM). Ofloxacin also inhibited the initial uptake of cephalexin and cephradine, which can be transported via the H+/organic cation antiport system in renal brush-border membranes. In contrast, ofloxacin had no effect on p-aminohippurate. These data suggest that ofloxacin interacts with the organic cation transport system in renal brush-border membranes, and this system may play an important role in the tubular secretion of ofloxacin.


Efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases: a randomized controlled trial.
The presence of bone metastases has excluded participation of prostate cancer patients in exercise intervention studies to date and is also a relative contraindication to supervised exercise in the community setting because of concerns of fragility fracture. However, this group of patients often have developed significant muscle atrophy and functional impairments from prior and continuing androgen deprivation that is exacerbated by subsequent and more intensive interventions such as chemotherapy. The aim of this study is to determine the efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases. Multi-site randomized controlled trial in Western Australia and New South Wales to examine the efficacy and safety of a modular multi-modal physical exercise program in 90 prostate cancer survivors with bone metastases. Participants will be randomized to (1) modular multi-modal exercise intervention group or (2) usual medical care group. The modular multi-modal exercise group will receive a 3-month supervised exercise program based on bone lesion location/extent. Measurements for primary and secondary endpoints will take place at baseline, 3 months (end of the intervention) and 6 months follow-up. Delaying or preventing skeletal complication and improving physical function for men with bone metastases would provide clinically meaningful benefits to patients. However, exercise programs must be designed and executed with careful consideration of the skeletal complications associated with bone metastatic disease and cumulative toxicities from androgen deprivation such as osteoporosis and increased risk of fractures. The results from this study will form the basis for the development of a specific exercise prescription in this patient group in order to alleviate disease burden, counteract the adverse treatment related side-effects and enhance quality of life. ACTRN: ACTRN12611001158954.


Comparison of four lung scoring systems for the assessment of the pathological outcomes derived from Actinobacillus pleuropneumoniae experimental infections.
In this study, four lung lesion scoring methods (Slaughterhouse Pleurisy Evaluation System [SPES], Consolidation Lung Lesion Score [LLS], Image analyses [IA] and Ratio of lung weight/body weight [LW/BW]) were compared for the assessment of the different pathological outcomes derived from an Actinobacillus pleuropneumoniae (App) experimental infection model. Moreover, pathological data was coupled with clinical (fever, inappetence and clinical score), production (average daily weigh gain [ADWG]) and diagnostic (PCR, ELISA and bacterial isolation) parameters within the four infection outcomes (peracute, acute, subclinically infected and non-infected). From the 61 inoculated animals, 9 were classified as peracute (presence of severe App-like clinical signs and lesions and sudden death or euthanasia shortly after inoculation), 31 as acutely affected (presence of App-like clinical signs and lesions and survival until the end of the experiment), 12 as subclinically infected (very mild or no clinical signs but App infection confirmed) and 9 as non-infected animals (lack of App-like clinical signs and lack of evidence of App infection). A significant correlation between all lung lesion scoring systems was found with the exception of SPES score versus LW/BW. SPES showed a statistically significant association with all clinical, production and diagnostic (with the exception of PCR detection of App in the tonsil) variables assessed. LLS and IA showed similar statistically significant associations as SPES, with the exception of seroconversion against App at necropsy. In contrast, LW/BW was statistically associated only with App isolation in lungs, presence of App-like lesions and ELISA OD values at necropsy. In conclusion, SPES, LLS and IA are economic, fast and easy-to-perform lung scoring methods that, in combination with different clinical and diagnostic parameters, allow the characterization of different outcomes after App infection.


Biomechanical properties of plate constructs for feline ilial fracture gap stabilization.
To determine the biomechanical properties of plating techniques for comminuted feline ilial fractures. Ex vivo study on 40 paired feline hemipelves. Forty paired fresh-frozen hemipelves that had been collected from 20 cats aged 2-6 years and weighing 4.0-5.5 kg. A transverse 3-mm gap was created in each ilium. Hemipelves were fixed with one of the following methods (n = 10 per group): (1) a dorsal plate and nonlocking screws, (2) a lateral plate and nonlocking screws, (3) a lateral plate and locking screws, or (4) a lateral and dorsal locking compression plate using nonlocking screws. Each specimen was subjected to incremental, sinusoidal cyclic loading until failure, defined as 10-mm displacement. The initial stiffness and number of cycles required to reach 1-, 2-, 5-, and 10-mm axial displacement were statistically analyzed. The initial stiffness and number of cycles to failure were higher in specimens fixed with double nonlocking plates than in all other fixations (P < .05) except specimens fixed with lateral locking plate at 10-mm displacement (P = .44). Locking implants withstood more cycles to 5- (P < .05) and 10-mm (P < .05) displacement compared with other single-plate nonlocking groups. Screw loosening occurred only in the 3 nonlocking fixations. Double plating improved stiffness and resistance to failure of comminuted feline ilial fracture constructs compared with all other fixations. Single locking plates produced superior constructs compared with single nonlocking constructs. Locking implants are recommended to repair comminuted feline ilial fractures for their extended fatigue life and resistance to screw loosening. Orthogonal plating offers a strong nonlocking alternative.


Physical activity and training in sarcoidosis: review and experience-based recommendations.
Sarcoidosis is a multisystemic inflammatory disorder with a great variety of symptoms, including fatigue, dyspnea, pain, reduced exercise tolerance and muscle strength. Physical training has the potential to improve exercise capacity and muscle strength, and reduce fatigue. The aim of this review and survey was to present information about the role of physical training in sarcoidosis and offer practical guidelines. A systematic literature review guided an international consensus effort among sarcoidosis experts to establish practice-basic recommendations for the implementation of exercise as treatment for patients with various manifestations of sarcoidosis. International sarcoidosis experts suggested considering physical training in symptomatic patients with sarcoidosis. Expert commentary: There is promising evidence of a positive effect of physical training. Recommendations were based on available data and expert consensus. However, the heterogeneity of these patients will require modification and program adjustment of the standard rehabilitation format for e.g. COPD or interstitial lung diseases. An optimal training program (types of exercise, intensities, frequency, duration) still needs to be defined to optimize training adjustments, especially reduction of fatigue. Further randomized controlled trials are needed to consolidate these findings and optimize the comprehensive care of sarcoidosis patients.


The therapeutic potential of milk thistle in diabetes.
Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.


Evaluation of a school based comprehensive sexuality education program among very young adolescents in rural Uganda.
Limited research has been conducted on the effectiveness of sexuality education for very young adolescents (VYAs) ages 10-14 years in Sub-Saharan Africa. Furthermore, evaluations of sexuality education programs often report outcomes of risky sexual practices, yet positive aspects of sexuality are hardly studied and rarely reported. This study evaluates the effectiveness of a Comprehensive Sexuality Education (CSE) intervention for VYAs in Uganda, analyzing both positive and negative outcome indicators. We conducted a mixed methods study, incorporating a cluster randomized trial (NCT03669913) among pupils in 33 randomly selected primary schools in Mbarara district. This was followed by a qualitative evaluation of the intervention in 4 schools that included 14 in-depth interviews and 3 focus group discussions distributed among pupils, teachers and parents. Quantitative data were analyzed using ordered logistic regression to compare differences in the change from baseline to endline between the intervention and control arms. We conducted bivariate analysis and multiple regression analysis controlling for key covariates, including age, gender, school location (rural vs urban), truancy, and orphanhood. Qualitative data were analyzed by thematic approach using ATLAS TI. Between July 2016 and August 2017, 1096 pupils were recruited. Outcomes were studied among 380 pupils in the intervention arm and 484 pupils in the control arm. The proportion of pupils who ever had sex increased from 9 to 12.1% in intervention compared to 5.2 to 7.4% in the control group between baseline and endline, however the differences between groups were not statistically significant. We found greater improvements in sexual and reproductive health (SRH) knowledge among intervention schools (AOR: 2.18, 95% CI: 1.66-2.86) and no significant differences in self-esteem, body image or gender equitable norms. Qualitative evidence echoes perceived SRH knowledge acquisition, increased their perception of SRH related risks, and intentions to delay sexual intercourse to prevent unwanted pregnancy, HIV and other STIs. This study demonstrates that CSE can improve SRH knowledge and behavioral intentions among VYAs in Uganda. These results further emphasize the importance of initiating sexuality education before most adolescents have started engaging in sexual activity, enabling them to make informed decisions in the future. NCT03669913 , registered retrospectively on September 13th, 2018.


Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility.
Over the last 10 years, genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for autoimmune diseases. However, despite increasing power for the detection of both common and rare coding variants affecting disease susceptibility, a large fraction of disease heritability has remained unexplained. In addition, a majority of the identified loci are located in noncoding regions, and translation of disease-associated loci into new biological insights on the etiology of immune disorders has been lagging. This highlights the need for a better understanding of noncoding variation and new strategies to identify causal genes at disease loci. In this review, I will first detail the molecular basis of gene expression and review the various mechanisms that contribute to alter gene activity at the transcriptional and post-transcriptional level. I will then review the findings from 10 years of functional genomics studies regarding the genetics on gene expression, in particular in the context of infection. Finally, I will discuss the extent to which genetic variants that modulate gene expression at transcriptional and post-transcriptional level contribute to disease susceptibility and present strategies to leverage this information for the identification of causal mechanisms at disease loci in the era of whole genome sequencing.


Repair of DNA-protein crosslink damage: coordinated actions of nucleotide excision repair and homologous recombination.
DNA-protein crosslinks (DPCs) are extremely bulky DNA lesions, and steric hindrance imposed by covalently trapped proteins would hamper the transaction of DNA such as replication, transcription, and repair. However, it has been largely elusive how cells mitigate the genotoxic effect of DPCs. We have recently shown that nucleotide excision repair (NER) and homologous recombination (HR) differentially contribute to the repair of DPCs in E. coli cells. Several lines of genetic and biochemical evidence indicate that NER repairs DPCs with crosslinked proteins (CLPs) of sizes less than 12-14 kDa, whereas DPCs with oversized CLPs are processed exclusively by RecBCD-dependent HR. The present result shows that cells use the coordinated actions of NER and HR to deal with unusually bulky DNA lesions like DPCs.


Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis.
Ovarian cryopreservation followed by autotransplantation is still considered an experimental strategy for fertility preservation (FP) mainly because the success rates are unknown. To determine cohort epidemiologic characteristics and success rates of autologous ovarian tissue transplantation (OTT) with previously cryopreserved tissue. Literature review from 1999 to October 1, 2016. Additional cases were retrieved from meeting abstracts and own database. We selected studies that reported autologous OTT with previously banked tissue in humans. We did not include any cases involving fresh ovarian tissue transplantation or those performed to treat idiopathic premature ovarian failure/insufficiency. Both authors reviewed and selected studies for eligibility, which resulted in 59 full-text studies assessed for eligibility. Cases were extracted from original reports and reviews by the junior author, and the senior author reviewed and verified the extracted data. Nineteen reports were included for qualitative synthesis. In 10 studies, detailed data were available to determine clinical and live birth + ongoing (LB + OG) pregnancy as well as endocrine restoration rates. Three hundred nine OTTs were performed with cryopreserved tissue, resulting in the birth of 84 children and 8 OG pregnancies. The cumulative clinical and LB + OG rates were 57.5% and 37.7%, respectively, and the endocrine restoration rate was 63.9%. Success rates with cryopreserved OTT have reached promising levels. Given these recent data, ovarian tissue cryopreservation should be considered as a viable option for FP.


Effect of ankle taping on knee and ankle joint biomechanics in sporting tasks.
Prophylactic taping is commonly used to prevent ankle injuries during sports. However, unnatural constraint of the ankle joint may increase the risk of injury to proximal joints such as the knee. The association between ankle taping and knee joint loading during open sporting tasks has not been quantified. This research aimed to measure changes in knee and ankle kinetics and kinematics during dynamic athletic activities undertaken with and without ankle taping. A kinematic and inverse dynamics model was used to determine ankle and knee joint motion and loading in 22 healthy male participants undertaking running and sidestepping tasks. Both tasks were randomized to planned and unplanned conditions and undertaken with and without the use of ankle tape. At the knee, peak internal rotation moments (P < 0.001) and peak varus moments (P < 0.05) were significantly reduced during all running and sidestepping trials (planned and unplanned) when undertaken with ankle tape. Internal rotation impulse (P < 0.001) was reduced for sidestepping tasks. Varus impulse during unplanned sidestepping maneuvers (P = 0.04) was reduced with the use of ankle tape. However, there was a trend toward increased valgus moments and impulse for planned sidestepping trials undertaken with ankle tape(P = 0.056). Taping reduced the range of motion at the ankle in all three planes (P < 0.05). Peak inversion (P < 0.001) was reduced for running trials only. Average eversion and peak dorsiflexion moments were significantly reduced in sidestepping tasks by use of taping. By limiting motion at the ankle, taping increased mechanical stability at this joint. Ankle taping also provided protective benefits to the knee via reduced internal rotation moments and varus impulses during both planned and unplanned maneuvers. Medial collateral and anterior cruciate ligament injuries may, however, occur through increased valgus impulse during sidestepping undertaken with ankle tape.


Analysis of atmospheric laser Doppler velocimeters.
Fundamental relationships between backscattered power, range, wavelength, and number of scatter centers in the probe volume for the self-aligning, dual-scatter, laser doppler velocimeter are developed. It is shown that not all power scattered from the velocimeter probe volume contributes to a doppler signal. This fact leads to significant deviations in calculations involving signal-to-noise power ratios as compared to the case when only gross backscattered power is considered.


Impaired fast-spiking interneuron function in a genetic mouse model of depression.
Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans.


Efficacy of Spa Therapy, Mud-Pack Therapy, Balneotherapy, and Mud-Bath Therapy in the Management of Knee Osteoarthritis. A Systematic Review.
Osteoarthritis (OA) is the most common musculoskeletal disease in the world. OA is the result of an inflammatory and degenerative process affecting the entire joint. Osteoarthritis, especially involving the knee, has a relevant socioeconomic impact in terms of drugs, hospital admissions, work absences, and temporary or permanent invalidity. Therapy of knee osteoarthritis is based on pharmacological and nonpharmacological measures. We conducted a systematic review of the studies published between 2002 and 2017 on spa therapy, mud-pack therapy, balneotherapy, and mud-bath therapy in the treatment of knee osteoarthritis in order to investigate the evidence of the efficacy of such treatment on pain, functional limitation, drug use, and quality of life. Overall, 35 studies were examined among which 12 were selected and included in the review if they are trial comparative. We have been able to illustrate the main results obtained in the individual studies and to elaborate these results in order to allow as much a unitary presentation as possible and hence an overall judgment. Because the studies we reviewed differed markedly from one another in terms of the methods used, we were unable to conduct a quantitative analysis (meta-analysis) of pooled data from the 12 studies. For the purposes of the present review, we reevaluated the results of the different studies using the same statistical method, Student's t-test, which is used to compare the means of two frequency distributions. Among all the studies, the most relevant indexes used to measure effectiveness of spa therapy were improved including VAS, Lequesne, and WOMAC Score. The mud-pack therapy, balneotherapy, mud-bath therapy, and spa therapy have proved to be effective in the treatment and in the secondary prevention of knee osteoarthritis, by reducing pain, nonsteroidal anti-inflammatory drug consumption, and functional limitation and improving quality of life of affected patients.


The effect of lipid demixing on the electrostatic interaction of planar membranes across a salt solution.
We study the effect of lipid demixing on the electrostatic interaction of two oppositely-charged membranes in solution, modeled here as an incompressible two-dimensional fluid mixture of neutral and charged mobile lipids. We calculate, within linear and nonlinear Poisson-Boltzmann theory, the membrane separation at which the net electrostatic force between the membranes vanishes, for a variety of different system parameters. According to Parsegian and Gingell, contact between oppositely-charged surfaces in an electrolyte is possible only if the two surfaces have exactly the same charge density (sigma(1) = -sigma(2)). If this condition is not fulfilled, the surfaces can repel each other, even though they are oppositely charged. In our model of a membrane, the lipidic charge distribution on the membrane surface is not homogeneous and frozen, but the lipids are allowed to freely move within the plane of the membrane. We show that lipid demixing allows contact between membranes even if there is a certain charge mismatch, /sigma(1)/ not equal /sigma(2)/, and that in certain limiting cases, contact is always possible, regardless of the value of sigma(1)/sigma(2) (if sigma(1)/sigma(2) < 0). We furthermore find that of the two interacting membranes, only one membrane shows a major rearrangement of lipids, whereas the other remains in exactly the same state it has in isolation and that, at zero-disjoining pressure, the electrostatic mean-field potential between the membranes follows a Gouy-Chapman potential from the more strongly charged membrane up to the point of the other, more weakly charged membrane.